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01-07-2019 | Alzheimer's Disease | Original Communication

Amyloid PETs are commonly negative in suspected Alzheimer’s disease with an increase in CSF phosphorylated-tau protein concentration but an Aβ42 concentration in the very high range: a prospective study

Authors: Chloé Manca, Thérèse Rivasseau Jonveaux, Véronique Roch, Pierre-Yves Marie, Gilles Karcher, Zohra Lamiral, Catherine Malaplate, Antoine Verger

Published in: Journal of Neurology | Issue 7/2019

Abstract

Background

Atypical cerebrospinal fluid (CSF) patterns, involving an increase in the concentration of phosphorylated-tau (P-tau) proteins but normal amyloid-β concentration, are not uncommon in patients with mild neurocognitive disorders and suspected Alzheimer’s disease (AD). In these conditions, however, AD diagnosis may be ruled out in the absence of any amyloid deposition at positron-emission tomography (PET). This pilot cross-sectional study was aimed to determine whether this negativity of amyloid PET can be predicted by CSF profiles in such patients.

Methods

Twenty-five patients (73 [68–80] years, 10 women) with mild neurocognitive disorders, suspected AD and an increase in the CSF concentration of P-tau proteins but normal Aβ42 concentration and Aβ42/Aβ40 ratio were prospectively included and referred to a ¹⁸F-florbetaben PET. The latter was considered as definitively negative with the conjunction of both visual (brain amyloid plaque load score) and quantified (standard uptake value ratios) criteria. Predictors of a negative PET were searched among current CSF biomarkers (Aß42, Aß40, T-tau, P-tau, Aß42/Aß40, Aß42/p-tau).

Results

Amyloid PET was negative in 15 patients (60%) with a CSF Aß42 concentration being the sole independent predictor of this negativity. The criterion of an Aß42 concentration in the very high range (> 843 pg/mL), observed in 60% (15/25) of the study patients, was associated with a negative amyloid PET in 93% (14/15) of cases.

Conclusions

In mild neurocognitive disorders patients with suspected AD and showing an increase in CSF P-tau protein level, amyloid PETs are commonly negative, when Aß42 concentration is in the very high range. In such case, AD diagnosis based on biomarkers can be ruled out with reasonable certainty, without the need for additional CSF second-line assays or results from amyloid PET.

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Jack CR, Bennett DA, Blennow K et al (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 14:535–562. https://doi.org/10.1016/j.jalz.2018.02.018 CrossRef

Koopman K, Le Bastard N, Martin J-J et al (2009) Improved discrimination of autopsy-confirmed Alzheimer’s disease (AD) from non-AD dementias using CSF P-tau (181P). Neurochem Int 55:214–218. https://doi.org/10.1016/j.neuint.2009.02.017 CrossRefPubMed

Sauvée M, DidierLaurent G, Latarche C et al (2014) Additional use of Aβ₄₂/Aβ₄₀ ratio with cerebrospinal fluid biomarkers P-tau and Aβ₄₂ increases the level of evidence of Alzheimer’s disease pathophysiological process in routine practice. J Alzheimers Dis JAD 41:377–386. https://doi.org/10.3233/JAD-131838 CrossRefPubMed

Gabelle A, Dumurgier J, Vercruysse O et al (2013) Impact of the 2008–2012 French Alzheimer plan on the use of cerebrospinal fluid biomarkers in research memory center: the PLM Study. J Alzheimers Dis JAD 34:297–305. https://doi.org/10.3233/JAD-121549 CrossRefPubMed

Sabri O, Sabbagh MN, Seibyl J et al (2015) Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: phase 3 study. Alzheimers Dement J Alzheimers Assoc 11:964–974. https://doi.org/10.1016/j.jalz.2015.02.004 CrossRef

Sabri O, Seibyl J, Rowe C, Barthel H (2015) Beta-amyloid imaging with florbetaben. Clin Transl Imaging 3:13–26. https://doi.org/10.1007/s40336-015-0102-6 CrossRefPubMedPubMedCentral

Pontecorvo MJ, Arora AK, Devine M et al (2017) Quantitation of PET signal as an adjunct to visual interpretation of florbetapir imaging. Eur J Nucl Med Mol Imaging 44:825–837. https://doi.org/10.1007/s00259-016-3601-4 CrossRefPubMed

Harn NR, Hunt SL, Hill J et al (2017) Augmenting amyloid PET interpretations with quantitative information improves consistency of early amyloid detection. Clin Nucl Med 42:577–581. https://doi.org/10.1097/RLU.0000000000001693 CrossRefPubMedPubMedCentral

Thurfjell L, Lilja J, Lundqvist R et al (2014) Automated quantification of 18F-flutemetamol PET activity for categorizing scans as negative or positive for brain amyloid: concordance with visual image reads. J Nucl Med 55:1623–1628. https://doi.org/10.2967/jnumed.114.142109 CrossRefPubMed

10.

Nayate AP, Dubroff JG, Schmitt JE et al (2015) Use of standardized uptake value ratios decreases interreader variability of [18F] florbetapir PET brain scan interpretation. AJNR Am J Neuroradiol 36:1237–1244. https://doi.org/10.3174/ajnr.A4281 CrossRefPubMedPubMedCentral

11.

Bullich S, Seibyl J, Catafau AM et al (2017) Optimized classification of18F-Florbetaben PET scans as positive and negative using an SUVR quantitative approach and comparison to visual assessment. NeuroImage Clin 15:325–332. https://doi.org/10.1016/j.nicl.2017.04.025 CrossRefPubMedPubMedCentral

12.

American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM-5^®). American Psychiatric Pub, Washington DCCrossRef

13.

McKhann GM, Knopman DS, Chertkow H et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 7:263–269. https://doi.org/10.1016/j.jalz.2011.03.005 CrossRef

14.

McKhann G, Drachman D, Folstein M et al (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34:939–944CrossRefPubMed

15.

Gervaise-Henry C, Watfa G, Albuisson E et al (2017) Cerebrospinal fluid Aβ42/Aβ40 as a means to limiting tube- and storage-dependent pre-analytical variability in clinical setting. J Alzheimers Dis JAD 57:437–445. https://doi.org/10.3233/JAD-160865 CrossRefPubMed

16.

Manca C, Hopes L, Kearney-Schwartz A et al (2019) Assessment of 18F-florbetaben amyloid PET imaging in patients with suspected Alzheimer’s disease and isolated increase in cerebrospinal fluid tau proteins. J Alzheimers Dis. https://doi.org/10.3233/JAD-181146 CrossRefPubMed

17.

Dumurgier J, Vercruysse O, Paquet C et al (2013) Intersite variability of CSF Alzheimer’s disease biomarkers in clinical setting. Alzheimers Dement 9:406–413. https://doi.org/10.1016/j.jalz.2012.06.006 CrossRefPubMed

18.

Lehmann S, Schraen S, Quadrio I et al (2014) Impact of harmonization of collection tubes on Alzheimer’s disease diagnosis. Alzheimers Dement J Alzheimers Assoc 10:S390–S394. https://doi.org/10.1016/j.jalz.2013.06.008 CrossRef

19.

Chetouani A, Chawki MB, Hossu G et al (2018) Cross-sectional variations of white and grey matter in older hypertensive patients with subjective memory complaints. NeuroImage Clin 17:804–810. https://doi.org/10.1016/j.nicl.2017.12.024 CrossRefPubMed

20.

Presotto L, Iaccarino L, Sala A et al (2018) Low-dose CT for the spatial normalization of PET images: a validation procedure for amyloid-PET semi-quantification. NeuroImage Clin 20:153–160. https://doi.org/10.1016/j.nicl.2018.07.013 CrossRefPubMedPubMedCentral

21.

Catafau AM, Bullich S, Seibyl JP et al (2016) Cerebellar amyloid-β plaques: how frequent are they, and do they influence 18F-florbetaben SUV ratios? J Nucl Med 57:1740–1745. https://doi.org/10.2967/jnumed.115.171652 CrossRefPubMed

22.

Barthel H, Gertz H-J, Dresel S et al (2011) Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 10:424–435. https://doi.org/10.1016/S1474-4422(11)70077-1 CrossRefPubMed

23.

Morris JC (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43:2412–2414CrossRefPubMed

24.

Fagan AM, Mintun MA, Mach RH et al (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ₄₂ in humans. Ann Neurol 59:512–519. https://doi.org/10.1002/ana.20730 CrossRefPubMed

25.

Forsberg A, Engler H, Almkvist O et al (2008) PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 29:1456–1465. https://doi.org/10.1016/j.neurobiolaging.2007.03.029 CrossRefPubMed

26.

Grimmer T, Riemenschneider M, Förstl H et al (2009) Beta amyloid in Alzheimer’s disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid. Biol Psychiatry 65:927–934. https://doi.org/10.1016/j.biopsych.2009.01.027 CrossRefPubMedPubMedCentral

27.

Tolboom N, van der Flier WM, Yaqub M et al (2009) Relationship of cerebrospinal fluid markers to 11C-PiB and 18F-FDDNP binding. J Nucl Med 50:1464–1470. https://doi.org/10.2967/jnumed.109.064360 CrossRefPubMed

28.

Jagust WJ, Landau SM, Shaw LM et al (2009) Relationships between biomarkers in aging and dementia. Neurology 73:1193–1199. https://doi.org/10.1212/WNL.0b013e3181bc010c CrossRefPubMedPubMedCentral

29.

Landau SM, Lu M, Joshi AD et al (2013) Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid. Ann Neurol 74:826–836. https://doi.org/10.1002/ana.23908 CrossRefPubMedPubMedCentral

30.

Tapiola T, Alafuzoff I, Herukka S-K et al (2009) Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol 66:382–389. https://doi.org/10.1001/archneurol.2008.596 CrossRefPubMed

31.

Lebouvier T, Pasquier F, Buée L (2017) Update on tauopathies. Curr Opin Neurol 30:589–598. https://doi.org/10.1097/WCO.0000000000000502 CrossRefPubMed

32.

Vlassenko AG, McCue L, Jasielec MS et al (2016) Imaging and cerebrospinal fluid biomarkers in early preclinical alzheimer disease. Ann Neurol 80:379–387. https://doi.org/10.1002/ana.24719 CrossRefPubMedPubMedCentral

Title: Amyloid PETs are commonly negative in suspected Alzheimer’s disease with an increase in CSF phosphorylated-tau protein concentration but an Aβ42 concentration in the very high range: a prospective study
Authors: Chloé Manca
Thérèse Rivasseau Jonveaux
Véronique Roch
Pierre-Yves Marie
Gilles Karcher
Zohra Lamiral
Catherine Malaplate
Antoine Verger
Publication date: 01-07-2019
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Alzheimer's Disease
Biomarkers
Published in: Journal of Neurology / Issue 7/2019
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-019-09315-y

ACC 2024 Congress

Springer Medicine

Amyloid PETs are commonly negative in suspected Alzheimer’s disease with an increase in CSF phosphorylated-tau protein concentration but an Aβ42 concentration in the very high range: a prospective study

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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